Last update 20 Jun 2024
TG-1801
Last update 20 Jun 2024
Overview
Basic Info
Drug Type Bispecific antibody |
Synonyms NI-1701, TG 1801 |
Target |
Mechanism CD19 modulators(B-lymphocyte antigen CD19 modulators), CD47 inhibitors(Cluster of differentiation 47 inhibitors) |
Therapeutic Areas |
Active Indication |
Inactive Indication- |
Originator Organization |
Active Organization |
Inactive Organization- |
Drug Highest PhasePhase 1 |
First Approval Date- |
Regulation- |
Gene Sequence
Sequence Code 17844712
Sequence Code 695525046
Sequence Code 695525049
Related
2
Clinical Trials associated with TG-1801A Phase 1b Multi-cohort Study of TG-1801 Alone or in Combination With Ublituximab in Subjects With B-Cell Lymphoma or Chronic Lymphocytic Leukemia
A Phase 1 First-in-Human Study of Bispecific Antibody TG-1801 in Subjects With B-Cell Lymphoma
100 Clinical Results associated with TG-1801
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100 Translational Medicine associated with TG-1801
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100 Patents (Medical) associated with TG-1801
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3
Literatures (Medical) associated with TG-180101 Jan 2023Frontiers in immunology
G protein-coupled receptor 183 mediates the sensitization of Burkitt lymphoma tumors to CD47 immune checkpoint blockade by anti-CD20/PI3Kδi dual therapy.
Article
Author: Normant, Emmanuel ; Armengol, Marc ; Roué, Gael ; Profitós-Pelejà, Núria ; Fernández-Serrano, Miranda ; Santos, Juliana Carvalho ; Blecua, Pedro ; Reyes-Garau, Diana ; Bosch, Francesc ; Ribeiro, Marcelo Lima ; Esteller, Manel ; Miskin, Hari P
Background:
Immunotherapy-based regimens have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decades; however, most disease subtypes remain almost incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory (R/R) B-NHL patients either as a single-agent or in combination with ublituximab, a new generation CD20 antibody.
Methods:
A set of eight B-NHL cell lines and primary samples were cultured in vitro in the presence of bone marrow-derived stromal cells, M2-polarized primary macrophages, and primary circulating PBMCs as a source of effector cells. Cell response to TG-1801 alone or combined with the U2 regimen associating ublituximab to the PI3Kδ inhibitor umbralisib, was analyzed by proliferation assay, western blot, transcriptomic analysis (qPCR array and RNA sequencing followed by gene set enrichment analysis) and/or quantification of antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP). CRISPR-Cas9 gene edition was used to selectively abrogate GPR183 gene expression in B-NHL cells. In vivo, drug efficacy was determined in immunodeficient (NSG mice) or immune-competent (chicken embryo chorioallantoic membrane (CAM)) B-NHL xenograft models.
Results:
Using a panel of B-NHL co-cultures, we show that TG-1801, by disrupting the CD47-SIRPα axis, potentiates anti-CD20-mediated ADCC and ADCP. This led to a remarkable and durable antitumor effect of the triplet therapy composed by TG-1801 and U2 regimen, in vitro, as well as in mice and CAM xenograft models of B-NHL. Transcriptomic analysis also uncovered the upregulation of the G protein-coupled and inflammatory receptor, GPR183, as a crucial event associated with the efficacy of the triplet combination. Genetic depletion and pharmacological inhibition of GPR183 impaired ADCP initiation, cytoskeleton remodeling and cell migration in 2D and 3D spheroid B-NHL co-cultures, and disrupted macrophage-mediated control of tumor growth in B-NHL CAM xenografts.
Conclusions:
Altogether, our results support a crucial role for GPR183 in the recognition and elimination of malignant B cells upon concomitant targeting of CD20, CD47 and PI3Kδ, and warrant further clinical evaluation of this triplet regimen in B-NHL.
01 Dec 2022Experimental Hematology & OncologyQ3 · MEDICINE
CD47xCD19 bispecific antibody triggers recruitment and activation of innate immune effector cells in a B-cell lymphoma xenograft model
Q3 · MEDICINE
ArticleOA
Author: Chatel, Laurence ; Cons, Laura ; Pontini, Guillemette ; Masternak, Krzysztof ; Moine, Valéry ; Daubeuf, Bruno ; Chauchet, Xavier ; Malinge, Pauline ; Chollet, Didier ; Didelot, Gérard ; Shang, Limin ; Buatois, Vanessa ; Ferlin, Walter
Abstract:
Background:
CD47/SIRPα axis is recognized as an innate immune checkpoint and emerging clinical data validate the interest of interrupting this pathway in cancer, particularly in hematological malignancies. In preclinical models, CD47/SIRPα blocking agents have been shown to mobilize phagocytic cells and trigger adaptive immune responses to eliminate tumors. Here, we describe the mechanisms afforded by a CD47xCD19 bispecific antibody (NI-1701) at controlling tumor growth in a mouse xenograft B-cell lymphoma model.
Methods:
The contribution of immune effector cell subsets behind the antitumor activity of NI-1701 was investigated using flow cytometry, transcriptomic analysis, and in vivo immune-cell depletion experiments.
Results:
We showed that NI-1701 treatment transformed the tumor microenvironment (TME) into a more anti-tumorigenic state with increased NK cells, monocytes, dendritic cells (DC) and MHCIIhi tumor-associated macrophages (TAMs) and decreased granulocytic myeloid-derived suppressor cells. Notably, molecular analysis of isolated tumor-infiltrating leukocytes following NI-1701 administration revealed an upregulation of genes linked to immune activation, including IFNγ and IL-12b. Moreover, TAM-mediated phagocytosis of lymphoma tumor cells was enhanced in the TME in the presence of NI-1701, highlighting the role of macrophages in tumor control. In vivo cell depletion experiments demonstrated that both macrophages and NK cells contribute to the antitumor activity. In addition, NI-1701 enhanced dendritic cell-mediated phagocytosis of tumor cells in vitro, resulting in an increased cross-priming of tumor-specific CD8 T cells.
Conclusions:
The study described the mechanisms afforded by the CD47xCD19 bispecific antibody, NI-1701, at controlling tumor growth in lymphoma mouse model. NI-1701 is currently being evaluated in a Phase I clinical trial for the treatment of refractory or relapsed B-cell lymphoma (NCT04806035).
01 Aug 2018Molecular cancer therapeuticsQ2 · MEDICINE
Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia
Q2 · MEDICINE
Article
Author: D'Asaro, Matilde ; Masternak, Krzysztof ; Ribera, José María ; Rettig, Michael ; Fielding, Adele K. ; Ritchey, Julie ; DiPersio, John F. ; Genescà Ferrer, Eulàlia ; Salgado-Pires, Susana ; Eissenberg, Linda ; LeGallou, Simon ; Fischer, Nicolas ; Kosco-Vilbois, Marie H. ; Matthes, Thomas ; Ferlin, Walter G. ; Johnson, Zoë ; Chauchet, Xavier ; Papaioannou, Anne ; Bailey, Katharine ; Broyer, Lucile ; Hatterer, Eric ; Tarte, Karin ; Clarke Hinojosa, Robert K. ; Cons, Laura ; Dey, Aditi ; Daubeuf, Bruno ; Fest, Thierry ; Barba, Leticia ; Buatois, Vanessa ; Richard, Françoise ; Shang, Limin
Abstract:
CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal “don't eat me” signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701–induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20–targeted therapy. Mol Cancer Ther; 17(8); 1739–51. ©2018 AACR.
2
News (Medical) associated with TG-180116 Jan 2021
AntibodyAccelerated ApprovalAcquisition
08 Jan 2021
AntibodyAccelerated ApprovalAcquisition
100 Deals associated with TG-1801
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R&D Status
10 top R&D records. to view more data
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| Indication | Highest Phase | Country/Location | Organization | Date |
|---|---|---|---|---|
| B-Cell Malignant Neoplasm | Phase 1 | CH | 30 Jan 2022 | |
| B-Cell Malignant Neoplasm | Phase 1 | CH | 30 Jan 2022 | |
| Chronic Lymphocytic Leukemia | Phase 1 | US | 23 Apr 2021 | |
| Follicular Lymphoma | Phase 1 | US | 23 Apr 2021 | |
| Mantle-Cell Lymphoma | Phase 1 | US | 23 Apr 2021 | |
| Marginal Zone B-Cell Lymphoma | Phase 1 | US | 23 Apr 2021 | |
| Mediastinal large B-cell lymphoma | Phase 1 | US | 23 Apr 2021 | |
| Small Lymphocytic Lymphoma | Phase 1 | US | 23 Apr 2021 | |
| B-Cell Lymphoma | Phase 1 | AU | 05 Mar 2019 |
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Clinical Result
Clinical Result
Indication
Phase
Evaluation
View All Results
Phase 1 | B-Cell Lymphoma CD19+ | CD47 | 30 | rmzupzndba(thwkgmvtzi) = ffgrbtvyfx sznqlmbuqb (obuwwnqvdx ) | Positive | 09 Jun 2023 | ||
TG-1801 + ublituximab combination therapy | ueywwlrgqa(ayvrhofrjj) = iycexzcusa tieoetnwla (wdgxnmdbur ) View more | ||||||
NCT03804996 (ASH2022) Manual  | Phase 1 | 30 | oaxkvzkqnq(tcmvtmammc) = 1 infusion reaction [500 mg monotherapy], 1 rash [360 mg monotherapy] zuqpoggjkl (mayyvgqtmc ) View more | Positive | 11 Dec 2022 | ||
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